12/18/2023 0 Comments Taghon notched up a level![]() Maturation of thymocytes then involves a complex interaction between transcription factors which control expression of Notch. In thymocytes, direct targets of Notch signalling such as HES1 are activated long before cell populations become committed to the T lineage, which demonstrates the lack of an early ‘lock down circuit’ or clear binary switch to the T cell fate. ![]() Myeloid fates are subsequently inhibited by the Notch signalling environment. At an early differentiation stage, these lymphoid-primed multipotent precursors lose erythrocyte/megakaryocyte potential and initiate the lymphoid gene program, whilst maintaining myeloid potential. After multipotent CD34 + HSCs leave the bone marrow, generation of the T lineage is triggered by entry into the Notch signalling environment of the thymus. Notch signalling promotes a range of cell differentiation programs including neuronal and vascular fates, ,, ,, , and it is reported to be essential in three aspects of haematopoietic cell differentiation: maintenance of HSCs, , initiation of the T cell lineage, ,, and maturation of CD4 and CD8 thymocytes. Understanding the mechanisms which drive T cell development is thus key to the development of strategies to improve transplant outcomes. While this is partly due to dependence on thymic activity, there is an intrinsic quality of adult cells which limits their T cell differentiation potential compared with CB cells in in vitro culture. HSC transplant is used to reconstitute the immune system after ablative therapy, but post-transplant the T cell lineage can be slow to recover. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported by a St Vincent's Clinic Research Foundation Grant, the John Kirkpatrick Research Fund, and the Maple-Brown Family Charitable Foundation. Received: MaAccepted: AugPublished: October 12, 2012Ĭopyright: © Carlin et al. ![]() University of California, San Francisco, United States of America We also identify gene expression profile differences that may account for low generation of T cells from adult HSCs.Ĭitation: Carlin SM, Khoo MLM, Ma DD, Moore JJ (2012) Notch Signalling Inhibits CD4 Expression during Initiation and Differentiation of Human T Cell Lineage. Notch signalling adds to signals provided by stromal cells to allow HSCs to differentiate to T cells via initiation of transcription factors such as HES1, GATA3 and TCF7. These results demonstrate that while Notch signalling is essential for establishment of the T cell lineage, at later stages of differentiation, its removal late in differentiation promotes more efficient DP cell generation. ![]() We identified a set of genes related to T cell development that were initiated by Notch signalling, and also a set of genes subsequently altered by Notch signal interruption. Interruption of Notch signalling in partially differentiated cells increased CD4 mRNA and protein expression, and promoted differentiation to CD4 + CD8 + T cells. Expression of the central thymocyte marker CD4 was initiated independently of Notch signalling, while cells grown with Notch signalling had reduced expression of CD4 mRNA and protein. Cells were also assayed for mRNA expression at critical developmental stages. Co-cultured cells were assayed at weekly intervals during development for phenotype markers using flow cytometry. This study investigates the contribution of Notch signalling and stromal support cells to differentiation of adult and Cord Blood (CB) human HSCs, using the Notch signalling OP9Delta co-culture system. This issue becomes central with observations that adult HSCs exhibit poor differentiation towards the T cell lineage relative to neonatal or embryonic precursors. Although T cell development is well characterized using expression of cell surface markers, the detailed mechanisms driving differentiation have not been established. The Delta/Notch signal transduction pathway is central to T cell differentiation from haemopoietic stem cells (HSCs).
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